Patent GB-1328321-A (GB)
Title: 2-heteroaryl benzimidazole derivatives useful as anthelmintics
IPC: C07F9/6558
Filed: 1971-04-19
Abstract: 1328321 2 - Heteroaryl - benzimidazole derivatives MERCK & CO Inc 19 April 1971 [5 March 1970] 22739/71 Headings C2C and C2P The invention comprises compounds of the Formula (I) in which X represents an oxygen or sulphur atom, R 1  represents a five-membered monocyclic heteroaromatic ring containing 1, 2 or 3 of the following hetero atoms, viz. oxygen, sulphur and nitrogen; R 2  represents alkyl, aralkyl, acyl carbamoyl, N-alkylcarbamoyl, alkoxycarbonyl, hydroxy, alkoxy, C 2-8  alkenyloxy carboxyalkoxy or an alkyl ester thereof, C 2-6  aminoalkoxy or an N-alkyl, N,N-dialkyl or trialkylammonium halide derivative thereof, C 2-6  diaminoalkoxy, phosphonalkoxy or an alkyl ester thereof, phosphatoalkoxy or an alkyl ester thereof, alkylthioalkoxy or a sulphoxide or sulphone derivative thereof, sulphoalkoxy, amidinoalkoxy or an N 1 - and/or N 2 - alkyl derivative thereof, 1-iminoalkylaminoalkoxy or an N-alkyl derivative thereof, (1- biguanido)alkoxy, guanidinoalkoxy or diaminomethyleneaminoalkoxy or an N 1 , N 2  and/or N 3  alkyl derivative thereof, aminoguanidinoalkoxy or N-aminodiaminomethyleneaminoalkoxy or an N<SP>1</SP>, N 1 , N 2  and/or N 3  alkyl derivative thereof, imidazolinylaminoalkoxy or a 1-alkyl derivative thereof, 1,4,5,6 - tetrahydropyrimidinylaminoalkoxy or a 1-alkyl derivative thereof, thiazolinylaminoalkoxy, thiazinylaminoalkoxy, imidazolinylalkoxy or a 1-alkyl derivative thereof, 1,4,5,6 - tetrahydropyrimidinylalkoxy or a 1-alkyl derivative thereof, acyloxy, α-aminocarboxyalkoxy, glycosyloxy, p-alkylphenacyloxy or p - lower alkoxyphenacyloxy, or a non-toxic alkali metal, alkaline-earth metal, magnesium, ammonium or pharmaceutically acceptable amine salt or heavy metal complex thereof when R 2  is carboxyalkoxy, sulphoalkoxy, phosphonoalkoxy, phosphatoalkoxy or α - aminocarboxyalkoxy; or a salt thereof with a pharmaceutically acceptable acid when R 2  is aminoalkoxy, amidinoalkoxy, 1-iminoalkylaminoalkoxy, (1-biguanido)alkoxy, guanidinoalkoxy, diaminomethyleneaminoalkoxy, aminoguanidinoalkoxy, N - aminodiaminomethyleneaminoalkoxy, imidazolinylaminoalkoxy, tetrahydropyrimidinylaminoalkoxy, thiazolinylaminoalkoxy, thiazinylaminoalkoxy, imidazolinoalkoxy, tetrahydropyrimidinoalkoxy or α - aminocarboxyalkoxy or whenever the R 2  group contains a free hydrogen; R 3  represents hydrogen or alkyl; R 4  represents hydrogen, cycloalkyl, aralkyl, haloaralkyl, monoalkylamino, dialkylamino, cycloalkylamino, alkyleneimino, hetero - interrupted alkyleneimino or a radical denoted by R-, RO- or RS- where R is a C 1-8  univalent aliphatic hydrocarbon, C 1-8  univalent aliphatic halohydrocarbon, aryl, haloaryl, heterocyclic, alkaryl or aminoaryl radical; and the alkyl and alkoxy residues in all the foregoing values of R 2  and R 3  are C 1-8  alkyl and C 1-8  alkoxy residues; with the proviso that when R 2  is alkyl, R 1  is not pyrazolyl. Compounds of Formula I in which R 2  is alkoxy, alkenyloxy, phosphonoalkoxy or an ester thereof, sulphoalkoxy, alkylthioalkoxy, imidazolinoalkoxy or a 1-alkyl derivative thereof, 1,4,5,6-tetrahydropyrimidinoalkoxy or a 1-alkyl derivative thereof, alkanoyloxy, α-aminocarboxyalkoxy, glycosyloxy, p - alkylphenacyloxy or p-alkoxyphenacyloxy, may be obtained by reacting a compound of the Formula (A) in the presence of a base with alkyl halide, an alkenyl halide, a haloalkanoic acid, an alkyl ester of a haloalkanoic acid, a haloalkylphosphonic acid or an alkali metal salt thereof, an alkyl ester of a haloalkylphosphonic acid, a haloalkylsulphonic acid or an alkali metal salt thereof, an alkylthioalkyl halide, an imidazolinoalkyl halide, a 1-alkylimidazolinoalkyl halide, a 1,4,5,6 - tetrahydropyrimidinoalkyl halide or a 1-alkyl derivative thereof, an alkanoic acid halide, an α-aminocarboxyalkyl halide, a glycosyl halide, an α-halo-p-alkoxy acetophenone or an α-halo-p-alkyl acetophenone. Compounds of Formula (I) in which R 2  is C 2-6  aminoalkoxy are obtained by reducing with hydrazine hydrate a compound of Formula (B) in which R 6  is C 2-6  alkylene (which may itself be obtained from (A) by reaction with N-halo- (C 2-6  alkyl)phthalimide. Compounds of Formula (I) wherein R 2  is imidazolylaminoalkoxy or 1,4,5,6 - tetrahydropyrimidinylaminoalkoxy or a 1-alkyl derivative thereof, thiazolinylaminoalkoxy, thiazinylaminoalkoxy or guanidinoalkoxy may be obtained by reacting a compound of Formula (C) with 2 - methylthio - 2 - imidazoline or 1,4,5,6- tetrahydropyrimidine or their 1-alkyl derivatives, 2 - methylthio - 2 - thiazoline or -2- thiazine or 2 - methyl - 2 - thiopseudourea. Compound (C) can be reacted with dicyandiamide to form (I) wherein R 2  is (1-biguanido)- alkoxy, or with nitroguanidine to form the 1-nitroguanidinoalkoxy benzimidazole which is catalytically reduced to form (I) wherein R 2  is aminoguanidinoalkoxy. Compound (C) N- substituted by R 12  which is H or C 1-8  alkyl reacts with an alkyl imino ester hydrochloride R 13 .C(=NH).OR 14 .HCl to form (I) in which R 2  is -O-R 6 -N(R 12 ).C(=NH).R 13  wherein R 13  is H or C 1-8  alkyl, and R 14  is C 1-8  alkyl. The preparation of the following intermediate is also described: 6-nitro-2-(4<SP>1</SP>-thiazolyl)benzimidazole and similar 2-thiadiazolyl-, pyrazolyl-, oxazolyl-, imidazolyl-, furyl-, and pyrrylbenzimidazoles and their reduction to corresponding 6 - amino - 2 - (heterocyclic)benzimidazoles. 6 - Nitro - 1 - hydroxy - 2 - (4<SP>1</SP>- thiazolyl)benzimidazole and corresponding 6 - amino compound; N - (2,4 - dinitrophenyl)- aminomethyl - 4 - thiazole; 2 - (4<SP>1</SP>- thiazolyl)- 6 - nitro - 1 - hydroxybenzimidazole and its 1 - methoxymethoxy derivative; and 1- methoxymethoxy - 6 - amino - 2 - (4<SP>1</SP> - thiazolyl)- benzimidazole. Anthelmintic compositions comprise compounds of Formula (I) above together with an inert diluent or carrier, in the form of a drench, or oral or injectable preparation or animal feedstuff.